JP2005046601A - Biodegradable hemostatic wound dressing - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a biodegradable hemostatic wound dressing showing hemostatic and antibacterial characteristics equivalent to or better than various conventional hemostatic wound dressings formed of carboxylic oxycellulose as a base material. <P>SOLUTION: The wound dressing utilizing a fibrous, fabric substrate made from a biocompatible polymer contains a first wound contact surface and a second surface opposing the first surface. The fabric has flexibility, strength and porosity effective for use as a hemostat. Further the wound dressing has a porous, polymeric matrix distributed at least on the first surface and through the fabric, and the porous, polymeric matrix is made of a biodegradable, biocompatible, water-soluble or water-swellable aldehyde-oxidized polysaccharide. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a hemostatic wound dressing comprising a fabric support and a porous, biocompatible, biodegradable, water-soluble or water-swellable polymer matrix.

  Bleeding management is essential and important in various surgical procedures to minimize blood loss, reduce postoperative complications, and reduce the duration of surgery within the surgical quality . Due to the biodegradability of cellulose and its bactericidal and hemostatic properties, cellulose that has been oxidized to include a carboxylic acid moiety, referred to below as carboxyl-oxidized cellulose, can be used in neurosurgery, abdominal surgery, cardiovascular surgery, It has long been used as a constant hemostatic wound dressing in various surgical procedures, including thoracic surgery, head and neck surgery, pelvic surgery and skin and subcutaneous tissue procedures.

  Currently used wound dressings for hemostasis include knitted or non-woven fabrics containing carboxylated cellulose. In addition, currently used oxidized regenerated cellulose is a carboxyl oxidized cellulose containing a reactive carboxylic acid group, and this cellulose is treated to enhance the homogeneity of cellulose fibers. Examples of such hemostatic wound dressings available on the market are Surgicel (R) absorbable hemostatic material, Surgery Nu-Knit (R) absorbable hemostatic material, and Includes Surgicel® fibrillar absorbable hemostatic material, all of which are from Johnson & Johnson Wound Management Worldwide (Ethicon, Inc.) Available from one division, Somerville, New Jersey, Johnson & Johnson Company). Another example of a commercially available hemostatic substance containing carboxylated cellulose is Oxycel® from Becton Dickinson and Company, Maurice Plains, NJ Includes absorbent cellulose surgical bandages. The above-mentioned hemostatic substance of oxidized cellulose is a knitted fabric having a certain porous structure effective for hemostasis. They exhibit good tension and compressive strength and are flexible so that certain physicians can manipulate the dressing during a particular procedure being performed with the hemostatic material effectively positioned.

  Accordingly, it would be advantageous to provide a hemostatic wound dressing that can be used in internal surgical procedures. In these procedures, the bioabsorbability and / or biodegradability of certain implants, such as certain hemostats, etc., can cause various reactions in the tissue where the remaining foreign material is undesirable. There are so important.

  The present invention provides biodegradable wound dressings that exhibit hemostatic and antibacterial properties equivalent to or better than various hemostatic wound dressings based on conventional carboxyl-oxidized cellulose. Yes.

  The invention relates to a wound dressing for hemostasis, the wound dressing including a fabric support, the fabric support comprising a first wound contact surface portion and the first wound contact. A second surface portion opposite to the wound contact surface portion of the fabric, wherein the fabric support includes a plurality of fibers and is also effective in use as a hemostatic substance, The fabric further includes a biocompatible polymer, and the wound dressing includes a porous polymeric matrix, the polymeric matrix comprising at least the first polymer. Distributed on the wound contact surface and in the fabric support, and the porous polymeric matrix is biocompatible, biodegradable, water soluble or water swellable Aldehyde-oxidized polysaccharides.

  Therefore, according to the present invention, biodegradable wounds exhibiting hemostatic and antibacterial properties equivalent to or better than various hemostatic wound dressings based on conventional carboxyl-oxidized cellulose. Can provide bandages.

  The inventor has discovered a wound dressing for hemostasis that utilizes a fabric as a support, in which case the fabric support is prepared from a biocompatible polymer. The wound dressing for hemostasis has, for example, strength, flexibility, and a plurality of fibers, a first wound contact surface portion, and a second surface portion opposite to the first surface portion. And various properties suitable for use as a hemostatic substance, such as porosity. A more detailed description of the fabric is given below. The wound dressing further includes a biodegradable and porous polymeric matrix, the polymeric matrix being disposed on at least the first wound contact surface portion and in the fabric support. Is distributed. Preferably, the porous polymeric substrate is further disposed on the second opposite surface portion. The polymeric substrate can also be substantially homogeneously disposed on the first wound contact surface portion and in the support. In addition, the second surface portion can also contact certain wounds or body tissue when placed on or in the body. The wound dressing for hemostasis of the present invention provides and maintains effective hemostasis when applied to certain wounds requiring hemostasis. This effective hemostasis, as used herein, is bleeding of capillaries, veins, or small arteries at a certain effective time, as recognized by those skilled in the art of hemostasis. The ability to adjust and / or alleviate In addition, various instructions for effective hemostasis can be provided by governmental regulatory standards.

  All Johnson & Johnson Wound Management Worldwide, a division of Ethicon, Inc., Johnson & Johnson Company, Somerville, New Jersey ( Surge Cell (R) Absorbable Hemostasis, Surgicel Nu-Knit (R) Absorbable Hemostasis, and Surgicel (available from Johnson & Johnson Company) ) (R) fibrillar absorbable hemostatic material and Oxycel (R) absorbable cellulose surgical dressing from Becton Dickinson and Company, Maurice Plains, NJ In conventional hemostatic wound dressings such as The various fabrics utilized can be used in the preparation of various wound dressings according to the present invention.

  In certain embodiments, the wound dressings of the present invention are effective in providing and maintaining hemostasis in the event of severe bleeding. As used herein, severe bleeding is meant to include such cases as bleeding where a relatively large amount of blood is lost at a certain relatively high rate. Examples of such serious bleeding include, without limitation, bleeding from arterial puncture, liver resection, obstructive liver injury, obstructive spleen injury, aortic aneurysm, bleeding from patients with excessive anticoagulation, or blood Includes bleeding from patients with coagulopathy, such as hemophilia. Such wound dressings allow certain patients to walk faster than current medical standards after, for example, certain diagnostic or therapeutic intravascular procedures.

  The composite hemostatic material of the present invention remains extremely flexible, conforms to certain bleeding sites, and maintains good tension and compressive strength to withstand handling during application. This hemostatic material can be cut into different sizes and shapes to suit the surgical needs. The hemostatic material can also be wrapped or packed into various irregular anatomical regions. The fabric in certain preferred embodiments capable of providing and maintaining effective hemostasis is Surge Cell Nu-Knit® available from Ethicon, Inc., Somerville, NJ. A certain knitted, carboxyl-oxidized regenerated cellulose, such as a fabric used to produce an absorbent hemostatic material.

  In certain embodiments of the invention, the wound dressing may further include various hemostatic agents or other biological or therapeutic substances, portions, or species including various drugs and agents that are not sensitive to acidity. Can be included. The above-mentioned acid-insensitive means that the above-mentioned substances are not useful for their intended purpose, such as carboxyl groups contained in various conventional carboxyl-oxidized cellulose wound dressings, etc. Means that it is not adversely affected by various acidic species such as Furthermore, the substance can be bound in the polymer matrix and in each surface portion of the fabric and / or in the fabric. These substances can also be combined by various chemical or physical means. In addition, these materials can be partially or homogeneously dispersed in the fabrics and / or polymeric substrates described above. Examples of these therapeutic substances include, but are not limited to, various analgesics, antibiotics, antibacterials, vasoconstrictors, antiadhesives, astringents and growth factors. A person skilled in the art will be able to add to the hemostatic wound dressing described herein a substance that is not sensitive to certain acidity after having benefited from the disclosure of the present invention. It is considered that sufficient information can be obtained.

  The fabric support utilized in the present invention is either woven or non-woven if the fabric has various physical properties necessary for use in various hemostatic wound dressings. You can also. Certain preferred woven fabrics have a constant density knitted structure that forms forms and shapes corresponding to various hemostatic wound dressings. Such fabrics are described in US Pat. No. 4,626,253, the contents of which are hereby incorporated by reference as if fully set forth.

In a preferred embodiment of the present invention, the absorbent hemostatic fabric is a warp knitted tricot fabric composed of transparent rayon twisted yarn, which is then oxidized to biodisintegrate into these fabrics. Contains a carboxyl or aldehyde moiety in an amount effective to confer sex and antimicrobial activity. These fabrics have a single layer thickness of at least about 0.5 mm, a constant density of at least about 0.03 g / cm ^2, an air porosity of less than about 150 cm ³ / sec / cm ² , and a dry weight of each fabric. Characterized by having at least about 3 times the liquid absorption capacity and at least about 0.1 g water absorption capacity per square centimeter of each fabric.

  The knitted fabrics have a good bulk count without undue weight, are soft and draped, and are well adapted to the shape of the surface portion to which these fabrics are applied. The fabric can also be cut into various suitable sizes and shapes without fraying or fraying along the cutting edge. Furthermore, the strength of the fabric after oxidation is suitable for use as a surgical hemostatic material.

  The preferred hemostatic fabric used in the present invention comprises oxidized cellulose and is best characterized by physical properties such as thickness, bulk coefficient, porosity and liquid absorption capacity as described above. . A suitable fabric having these characteristics can be constructed by knitting 60 denier 18 filament filament transparent rayon yarn using a constant 32 gauge device at a constant knitting quality of 12. Certain tricot fabric configurations have a front bar of 1-0, 10-11 and a back bar of 2-3, 1-0. This extended swing applied to the front bar results in a constant 188 inch (477.52 cm) runner versus a constant 70 inch (177.8 cm) runner corresponding to the back guide bar. This increases the bulk coefficient and density of the fabric. Therefore, the ratio value of the runner to the back bar of the front bar in such a specific configuration is 1: 2.7.

Typical physical and hemostatic properties of preferred fabrics produced as described above are set forth in Table 1 below.

  The tricot fabric utilized in the present invention can be composed of transparent rayon twisted yarn having a total denier value of about 40-80. Further, each strand may contain 10 to 25 individual filaments, but each individual filament is preferably lower than 5 denier to avoid extended absorption times. Also, high bulk modulus and fabric density can be obtained by knitting at 28 gauge or less, preferably 32 gauge, with a fabric quality of about 10 or 12 (40 to 48 cross stitches). Also, the thickness and density of the fabric can be further increased by a constant long guide bar swing in the interval of at least 6 needles, preferably 8-12.

  Of course, other warp knitted tricot fabrics that exhibit comparable physical properties are also available in the manufacture of various improved hemostatic fabrics and wound dressings of the present invention, and these configurations are known in the art. It becomes clear to the expert.

  Polymers useful in the preparation of the fabric support in the wound dressings of the present invention include, without limitation, collagen, calcium alginate, chitin, polyester, polypropylene, polysaccharides, various polyacrylic acids, polymethacrylic acid, polyamines, Polyimine, polyamide, polyester, polyether, polynucleotide, polynucleic acid, polypeptide, protein, poly (alkylene oxide), polyalkylene, polythioester, polythioether, polyvinyl, polymers containing various lipids, and these A mixture of

  Preferably, various carboxylated polysaccharides are used to prepare the wound dressing of the present invention. More preferably, carboxylated cellulose is used to prepare the fabric used in the wound dressing of the present invention. More preferably, carboxyl-oxidized regenerated cellulose is used to prepare the fabric used in the wound dressing of the present invention. Such regenerated cellulose is believed to be preferred due to a higher degree of uniformity than unregenerated cellulose. It should be noted that certain detailed descriptions of methods for making such regenerated cellulose and regenerated carboxyl-oxidized cellulose are described in US Pat. No. 3,364,200 and US Pat. No. 5,180,398, Each of these contents is hereby incorporated by reference as if fully set forth. Accordingly, the teachings relating to regenerated oxidized cellulose and methods of making the same are well known to those skilled in the art of hemostatic wound dressings.

  Certain wound dressings of the present invention utilize various fabric supports that have been oxidized to include a carboxyl moiety in an amount effective to provide the fabric described above with biodegradable and antimicrobial activity. Yes. U.S. Pat. No. 3,364,200 discloses the preparation of carboxylated cellulose with certain oxidizing agents such as dinitrogen tetroxide in certain Freon media. U.S. Pat. No. 5,180,398 also discloses the preparation of carboxylated cellulose with certain oxidizing agents such as nitrogen dioxide in certain perfluorocarbon solvents. After oxidation by any of the above methods, the fabric is thoroughly washed with a certain solvent such as carbon tetrachloride, then with an aqueous solution of 50% isopropyl alcohol (IPA), and finally 99. Washed with% IPA. Also, prior to oxidation, the fabric is configured as a desired woven or non-woven structure suitable for use as a hemostatic substance. It has been found that certain wound dressings according to the present invention utilizing such fabrics can stop and maintain hemostasis in case of severe bleeding.

  Also, a saturation and lyophilization treatment with a polymer solution as described herein in order for the fabric to have a substantially homogeneous distribution of the polymer solution on and within the substrate of the fabric. It has also been found preferable that the condition has been adjusted before. The fabric conditioning can be accomplished by storing at room temperature under various ambient conditions for at least 6 months, or the fabric conditioning can be accelerated. Preferably, the fabric is exposed to conditions of about 4 ° C. to about 90 ° C. at a constant relative humidity of about 5% to about 90% for a time of about 1 hour to 48 months. More preferably, the fabric is exposed to conditions of about 4 ° C. to about 60 ° C. at a constant relative humidity of about 30% to about 90% over a period of about 72 hours to 48 months. More preferably, the fabric is exposed to conditions of about 18 ° C. to about 50 ° C. at a constant relative humidity of about 60% to about 80% for a period of about 72 hours to 366 hours. Most preferably, the fabric is conditioned at a constant temperature of about 50 ° C. at a constant relative humidity of about 70% over a period of about 168 hours. It should be noted that the fabric can be placed horizontally in a constant adjustment environment, but care must be taken to provide spacing between the fabric supports to allow proper adjustment. There is a need. The fabric can also be hung vertically to allow adjustment.

  As a result of the preparation of the carboxylated cellulose fabric support, the fabric support is at least about 3 wt%, preferably about 3 to about 30 wt%, more preferably about 8 to about 20 wt%, more preferably Contains from about 9 to about 12% by weight, most preferably about 10% by weight of various water-soluble molecules. In general, these water-soluble molecules are acid-substituted oligosaccharides containing about 5 or less sugar ring structures. It should be noted that the hemostatic efficacy of wound dressings including the support of a carboxy-oxidized cellulose fabric as described above, including the occurrence of rebleeding in certain wounds where hemostasis was initially achieved is It has been found that the amount improves when it reaches about 8%, preferably about 10%, based on the weight of the fabric support.

  The fabric support used in the present invention also contains about 3 to about 20 weight percent water, preferably about 7 to about 13 weight percent, more preferably about 9 to about 12 weight percent water.

  Similar amounts of moisture and water soluble molecules in the above carboxylated cellulose fabric support can also be achieved by other means. For example, sterilization of the fabric by a variety of known techniques, such as gamma or electron beam irradiation, can provide a similar content of water and / or water soluble molecules. In addition, various water soluble molecules such as oligosaccharides can be added to the fabric prior to distribution of the porous polymeric matrix on or in the fabric. Furthermore, after receiving the benefits of such disclosure, those skilled in the art can readily ascertain alternative methods for supplying moisture and / or various water soluble molecules to such fabrics. It becomes possible.

  As noted above, the wound dressing of the present invention is a biodegradable, porous material that is disposed on at least the first wound contact-like surface portion and is dispersed within the fabric support. Of a polymeric substrate. Preferably, the substrate is also disposed on the second opposite surface portion. It is also possible that the polymer matrix is homogeneously disposed on both the first and second surface portions and is dispersed in the fabric. Further, the polymer used to prepare the porous polymer matrix in the wound dressing of the present invention is a certain biocompatible, biodegradable, water-soluble or water-swellable aldehyde-oxidized polysaccharide. It is. Such water-soluble or water-swellable polysaccharides absorb blood or other various body fluids quickly, and when placed in contact with the tissue, they adhere to the tissue. Alternatively, a sticky gel is formed. In addition, the fluid-absorbing polysaccharide interacts with body fluids through a certain hydration process when in a certain dry state or concentrated state. That is, when supplied to a certain bleeding site, the polysaccharide interacts with water components in the blood through a hydration process. In addition, this hydration power creates a certain adhesive interaction that helps the hemostatic substance adhere to the site of bleeding. Further, this adhesion forms a certain sealing layer between the hemostatic substance and the bleeding site and stops the blood flow.

  The polysaccharide capable of aldehyde oxidation according to the present invention includes, without limitation, cellulose, for example, alkyl cellulose such as methyl cellulose, hydroxyalkyl cellulose, alkylhydroxyalkyl cellulose, cellulose sulfate, carboxymethyl cellulose salt. , Cellulose derivatives such as carboxymethyl cellulose and carboxyethyl cellulose, chitin, carboxymethyl chitin, hyaluronic acid, hyaluronic acid salt, alginate, alginic acid, propylene glycol alginate, glycogen, dextran, dextran sulfate, kudran Pectin, pullulan, xanthan, chondroitin, chondroitin sulfate, carboxymethyl dextran, carboxymethyl chitosan, heparin, Heparin sulfate, including heparan, heparan sulfate, dermatan sulfate, keratin sulfate, carrageenans, chitosan, starch, amylose, amylopectin, poly -N- glucosamine, polymannuronic acid, polyglucuronic acid, polyguluronic acid and mixtures and derivatives thereof.

  In wound dressings as described above, the aldehyde-oxidized polysaccharide contains a certain amount of aldehyde moiety that is effective to render the modified polysaccharide biodegradable, which means that the polysaccharide is resorbed by the body. It means that it can be or can be broken down by the body into various components that can easily pass through in the body. In particular, these biodegraded components do not show a permanent chronic foreign body reaction when absorbed by the body, and no permanent traces or residues of that component are retained at the implantation site.

In preferred embodiments utilizing aldehyde oxidized polysaccharides, the polysaccharide is oxidized as described herein to ensure that the aldehyde oxidized polysaccharide is biodegradable. Has been. Such biodegradable aldehyde-oxidized polysaccharides can be represented by the following structure I:
In this case, x and y indicate mol% values, x + y is equal to 100%, x is from about 95 to about 5, y is from about 5 to about 95, R is CH ₂ OR ₃ , COOR ₄ , sulfonic acid, or phosphonic acid, R ₃ and R ₄ are H, alkyl, aryl, alkoxy or aryloxy, R ₁ and R ₂ are H, alkyl, aryl, alkoxy, aryloxy, sulfonyl or Can be phosphoryl.

  An exemplary method of making the wound dressing of the present invention is described below. The steps involved in the preparation of the novel porous structure described above include the process of dissolving the lyophilized polymer in a suitable solvent corresponding to a suitable polymer to prepare a homogeneous polymer solution. Including. Thereafter, the fabric comes into contact with the polymer solution and is saturated with the polymer solution. The fabric support and polymer solution contained in the fabric's dense construction are then subjected to a freeze and vacuum drying process. During this freeze / dry process step, the solvent is removed by sublimation, leaving a porous polymer matrix structure disposed on or in the fabric support. Such a preferred lyophilization process results in a wound dressing having a fabric support comprising a substrate of a water-soluble or water-swellable polymer having a microporous and / or nanoporous structure. These lyophilization conditions create a large substrate surface area within the hemostatic material with which various body fluids can interact when the dressing is applied to a wound that requires hemostasis. In particular, it is important in the above novel porous structure.

  During the lyophilization process described above, several parameters and procedures are important for producing wound dressings with various mechanical properties that are suitable for use in hemostatic wound dressings. The features of the microporous structure as described above can be adjusted to suit certain desired applications by selecting appropriate conditions for forming a composite hemostatic material during the lyophilization process. The type of microporous morphology that develops during this lyophilization process is a constant function of various factors such as solution thermodynamics, freezing rate, temperature at which the solution freezes, and concentration of the solution. In order to maximize the surface area of the porous substrate of the present invention, certain preferred methods rapidly freeze the fabric / polymer structure described above at a temperature below 0 ° C, preferably about -50 ° C, and The removal of the solvent in a high vacuum. The porous substrate produced thereby gives the hemostatic wound dressing a certain large fluid absorbency capability. When the hemostatic wound dressing comes into contact with body fluids, a certain very large surface area polymer is quickly exposed to the fluid. Furthermore, the hydrating power of the hemostatic substance and the subsequent formation of a sticky, gelatinous layer helps to form a cohesive interaction between the hemostatic substance and the bleeding site. The microporous structure of the polymeric matrix also allows blood to pass quickly through the surface of the fabric before the hydration occurs, so that a constant and increased amount of polymer contacts various body fluids. To come. Also, the formation of a certain gelatinous sheet on oxidized cellulose upon blood contact enhances its water-soluble and gelatinous layer sealing or sealing properties, which is the case for moderate to severe bleeding In order to stop bleeding quickly.

  In some embodiments in the case of severe bleeding, the fabric support comprises the biodegradable polymer in an amount effective to effect and maintain effective hemostasis. If the polymer to fabric ratio is too low, the polymer will not form an effective seal to physically block bleeding, thereby reducing hemostatic properties. Also, if the ratio is too high, the composite hemostatic wound dressing becomes too stiff or too brittle in conformity to the wound tissue in various surgical applications, thereby placing and manipulating the dressing Adversely affects the mechanical properties required for the doctor to handle. Such an excess ratio is also important for enhancing the sealing properties. Blood rapidly passes the surface of the fabric to form a gelatinous layer on the oxidized biodegradable cellulose. Disturb that. A certain preferred weight ratio of polymer to fabric is from about 1:99 to about 15:85. In addition, a preferred ratio of this polymer to fabric is about 3:97 to 10:90.

The wound dressing of the present invention can best be illustrated in various images prepared by scanning electron microscope. These samples are prepared by cutting a 1 cm ² portion of each bandage using a regular razor. In addition, micrographs of both the first surface and the opposite second surface, as well as the cross-section, were prepared and mounted on a carbon mount using carbon paint. Further, these samples were subjected to gold sputtering treatment and examined with a scanning electron microscope (SEM) under high vacuum at 4 KV.

  FIG. 1 is a cross-section of an uncoated carboxyl-oxidized regenerated cellulose fiber 12 organized as a plurality of fiber bundles 14 and knitted into a fabric 10 in accordance with various preferred embodiments of the present invention described above. It is a figure (75 times). An example of such a commercial fabric is the Surgicel Nu-Knit (R) absorbable hemostatic wound dressing.

  FIG. 2 is a view of a first surface portion of the fabric of FIG. Individual fibers 12 are shown in a bundle.

  FIG. 3 shows a fabric 20 without a lyophilization process, having a first wound contact surface portion 22 and an opposite surface portion 24, which is dried after being saturated with a solution of a polymer. FIG. Individual fibers 23 are also shown.

  FIG. 4 is a view of the surface portion 22 of the fabric 20. As observed in this figure, along the air drying path, the polymer 26 clumps and adheres to the fibers 23, and in many cases, these fibers 23 adhere to each other and various body fluids are formed. A number of spaces 28 are formed in the hemostatic fabric that can be passed. The polymer 26 dispersed on and in the fabric 20 is not in a porous matrix and is therefore an effective polymer / body fluid effective to stop and maintain hemostasis in the event of severe bleeding. At least partially lacking in sufficient porosity, such as surface area, for example, to cause an interaction will completely prevent hemostasis in the case of severe bleeding as described herein above. Don't do it.

  FIG. 5 is a view of the surface portion 24 on the opposite side of the fabric 20. As shown, this opposite surface portion 24 includes a relatively large concentration of polymer coating material as opposed to the surface portion 22 shown in FIG. 4, so that most fibers 23 are obscured. However, the pattern of knitting can be identified. This coating is thick enough to spread across all the fibers, forming its own untreated layer 27, which is also shown in FIG. This layer is considered brittle and multiple cracks 29 are seen in the coating. Further, the thickness of the coating layer is about 3 microns thin in some parts, and is changed to about 30 to 65 microns in other parts.

  In comparing the surface morphology of the surface portion 22 of the fabric 20 and the surface portion 24 on the opposite side, it is clear that the surface portion 22 contains considerably less polymer. Also, the coating is considerably thinner on each fiber than the coating on the opposite surface portion. In addition, some polymers are observed to spread across some fibers, but the coating is incomplete or has multiple holes. The thickness of this coating layer, when present, does not exceed about 2 microns.

  3 to 5, it is clear that the fabric prepared by the air drying process does not contain a porous polymer matrix that is homogeneously dispersed on and in each surface. These fabrics are brittle and hard, do not conform to the wound site, cannot be handled by a doctor, and are generally not suitable for use as wound dressings.

  Meanwhile, a hemostatic fabric containing aldehyde-oxidized methylcellulose as the polymer substrate according to the present invention is illustrated in FIGS. As shown in FIGS. 6 and 7, a porous polymeric substrate is distributed over the wound contact surface portion 32 and the opposite surface portion 34 and in the fabric 30. This polymer 36 forms a certain porous substrate integrated by knitted fibers 33. This porous polymer matrix exhibits significant liquid absorption properties by capillary action in a manner similar to certain sponges.

  As shown in FIG. 7, the polymer matrix disposed over the surface portion 32 has a myriad of pores ranging in diameter from about 2 microns to about 35 microns or more. Have. As mentioned above, the polymer 36 is present in the form of a porous matrix around each fiber 33, which provides the necessary and sufficient surface area of the polymer that can interact when various body fluids contact the surface. Forming. The opposite surface 34 shown in FIG. 8 also includes a polymer 36 in the form of a porous substrate.

  In addition, a hemostatic wound dressing made from carboxylated regenerated cellulose according to the present invention and a biodegradable polymeric aldehyde oxidized hydroxyethyl cellulose are shown in FIGS.

  As shown in FIG. 9, a porous polymeric matrix is distributed over the respective surface portions 42 and 44 and in the fabric 40. The polymer 46 forms a porous polymer matrix that is integrated by knitted fibers 43. This porous polymer matrix exhibits significant liquid absorption properties by capillary action in a manner similar to certain sponges.

  As shown in FIGS. 10 and 11, the polymer substrate disposed on the respective surface portions 42 and 44 has a diameter in the range of about 10 microns to about 400 microns or more. Has countless pores. FIG. 10 shows the surface portion 42 of the fabric 40. As mentioned above, the polymer 46 is present in the form of a porous matrix around each fiber 43, thereby forming a necessary and sufficient surface area of the polymer that can interact when various body fluids contact the surface. is doing. The opposite surface 44 shown in FIG. 11 also includes a polymer 46 in the form of a porous substrate.

  6-11 show that the fabrics and wound dressings of the present invention include a porous polymeric matrix that is dispersed substantially over the respective surface portion and within the fabric. It is. Due to the porous nature of the matrix, various body fluids can flow into the matrix, in which case the necessary and sufficient surface area of the polymer exists to interact with the body fluid. This allows relatively rapid and relatively high hemostasis.

  Also, according to FIGS. 3-5, each comparative fabric and wound dressing does not contain a porous polymer matrix dispersed on or in a surface portion of the bandage. Is also obvious. As a result of this, the amount of polymer present to interact with various body fluids is significantly reduced. In addition, the formation of a clumped polymer layer during the air drying process prevents free entry of various body fluids into the bandage so that it can interact and bind to the wound dressing. . In addition, these fabrics have been found to be brittle and stiff, making it unacceptable for placement by and conformance to certain wound sites by certain physicians.

  As noted above, to maintain the porous structure of the polymer matrix and its homogeneity, to avoid defects on and in the wound dressing, the process during the process of creating the wound dressing It is important to maintain a preferred weight ratio of polymer to fabric and a homogenous distribution of the polymer solution on and in the surface of the fabric support.

  In certain laboratory equipment, the fabric support is contacted with the polymer solution in the laboratory crystallization dish to saturate the fabric support material in the polymer solution and then the fabric support. And by lyophilizing the solution in the dish, the above is easily accomplished, in which case a precise amount of water-soluble and water-swellable is used to prepare the solution. Polymers can be used. In this case, it is not absolutely necessary to transfer the saturated fabric or dish into a freeze-drying apparatus. As a result of this, a uniform distribution of the polymer in the fabric is achieved. However, in a certain manufacturing facility, due to its relatively large scale, the above-described processing becomes impossible. Certain relatively large containers, such as trays or pans, are used instead to hold the fabric and polymer during contact and saturation of the fabric with the solution, and this treatment is outside the lyophilizer. Performed in This saturated fabric then needs to be transferred into a lyophilizer for further processing.

  There are particular problems associated with producing certain wound dressings of the present invention on a relatively large scale as described above, where the wound dressing is suitable for use as a hemostatic bandage. Has mechanical and hemostatic properties. For example, when attempting to move a container containing the polymer solution and a saturated fabric disposed therein into a lyophilizer, during the transfer of the container into the lyophilizer, for example, Movements such as displacement or "sloshing" with respect to the fabric make it difficult to maintain a certain amount of polymer solution above the fabric in the tray. In some cases during the movement of the container, the surface portion of the fabric is exposed and disturbance of the polymer solution in the container causes the polymer on and within the fabric, in particular the polymer on the surface portion. Insufficient distribution in the distribution. This is further detrimental to the effect of the hemostatic properties of the wound dressing.

  To ensure that the fabric remains immersed in the polymer solution to form a homogeneous distribution on and in the fabric, the solution above the fabric is prior to lyophilization. In order to maintain the volume, a certain excess of polymer solution needs to be placed in the container. However, such a method is not effective because an excess of polymer solution as described above can result in a certain undesired polymer to weight ratio, and such undesired weight ratio results in damage to the wound. The bandage lacks flexibility and impairs the structure of the micropores in the polymer matrix of the hemostatic wound dressing.

  In order to eliminate such problems, the method of the present invention can be used, for example, to transfer a saturated fabric from a container used to saturate the fabric with a polymer solution into a freeze-drying apparatus. A certain transport support means such as a sheet or a carrier is used. However, to maintain a homogeneous distribution of the porous polymeric matrix on and in the fabric support after the lyophilization process, minimizing disruption of the homogeneous distribution of the polymer solution to the fabric; Care must be taken to minimize deformation, such as stretching or tearing, of the fabric support during transport into the lyophilizer. In addition, during the transfer of the fabric to the support means, the formation of bubbles or bubbles between the fabric support and the transfer support means is substantially avoided and is not acceptable in the wound dressing. It is necessary not to form a number of defective portions.

  In accordance with the present invention, the method transfers the saturated fabric support to the transfer support means and transfers the saturated fabric support and support means to a freeze-drying apparatus. Do things.

  Transfer of the saturated fabric onto the support means provides a constant fluid pressure sufficient to allow air bubbles to escape between the fabric support and the support means. Achieved in style. The leading end of the fabric is connected to the support means and moves in a constant and continuous manner at a constant adjusted speed, so that its base end is also protected to prevent or at least minimize bubble formation. A constant desired dosing angle between the fabric and the support means is maintained until supported by the support means. At the same time, maintaining the transfer conditions as described above prevents or at least minimizes physical deformation of the support such as stretching or tearing. Preferably, the dosing angle between the fabric and the support means is in the range of about 20 ° to about 90 °. More preferably, this dosing angle ranges from about 30 ° to about 60 °. More preferably, this throw angle is about 45 °. Also, the rate of progression of the fabric onto the support means is preferably in the range of about 8 inches (20.3 centimeters) / minute to about 2 inches (5.1 centimeters) / minute. More preferably, this transfer rate is about 7 inches (17.8 centimeters) / minute.

  The support means should be made of an inert material that does not release any toxic chemicals or any substances that may change the properties of the wound dressing. It is also important that this support means does not change the various parameters of freezing and drying associated with the lyophilization process described above. Therefore, the material used for this support means must be stable in the cold state and can withstand very low temperatures, preferably on the order of about -50 ° C., without deformation. If the support means is not stable at low temperatures, deformation of the means will cause defects in the wound dressing.

  The support means used to transport the saturated fabric has a density, mechanical strength, flexibility and thickness to provide sufficient support for the fabric, and the saturated fabric. It is important to tear the bending and mechanical deformation of the support. If the support means is excessively thick and rigid, it may be difficult to slide a saturated fabric over the support means. Also, if the support means is excessively soft and flexible, the saturated fabric may bend excessively, resulting in elongation or other mechanical deformation, which is a polymer solution on the surface. Can build up or flow or form surface defects during lyophilization.

  It is also important that the support means used to transport the fabric support has a constant smooth and flat surface to prevent air bubbles from being trapped under the saturated fabric support. is there. This transfer means further provides rapid freezing of the fabric / polymer structure to maintain a homogeneous distribution of the porous polymer matrix on and in the fabric support after lyophilization. And having a heat transfer efficiency suitable for removal of the solvent under high vacuum in the lyophilizer. This heat transfer efficiency means that heat is quickly transferred from the support means to the saturated fabric to facilitate quick freezing. A preferred support means is a high density polyethylene sheet having a preferred thickness of about 50 mils to about 200 mils. The most preferred support means is high density polyethylene having a constant preferred thickness of about 60 mils to about 100 mils.

  The following examples illustrate specific embodiments of the present invention, but they should not be construed as limiting the scope of the invention, but rather contribute to a certain complete description of the invention. Should be interpreted as being.

Example 1:
Preparation of water-soluble aldehyde oxidized methylcellulose (AOMC) 3 g of an aqueous solution of 100 g of 5% methylcellulose (MC, average molecular weight: 14 kilodalton (kD), lot number: 13517 LO, Aldrich, Milwaukee, Wis.) After mixing with periodic acid (Aldrich, Milwaukee, 53201), it was stirred for 5 hours at ambient temperature in the dark. Next, 1.5 ml of ethylene glycol was added to the reaction solution and stirred for 30 minutes. Thereafter, 2000 ml of acetone was gradually added to the reaction solution to precipitate aldehyde oxidized methylcellulose (AOMC). Further, the reaction mixture was left for 20-30 minutes to separate the liquid phase from the solid phase. Thereafter, the supernatant was removed and the solid phase was centrifuged to precipitate a solid. The solid precipitate was then dissolved overnight in 100 ml deionized water (DI) and dialyzed for 72 hours. In addition, the final wet mixture was lyophilized to form a sponge / foam.

Example 2:
Preparation of water-soluble aldehyde oxidized hydroxyethyl cellulose (AOHEC) 3 g of an aqueous solution of 100 g of 5% hydroxyethyl cellulose (HEC, average molecular weight: 90 kD, lot number: 04220MS, from Aldrich, Milwaukee, Wis.) With periodic acid (Aldrich, Milwaukee, 53201) and stirred in the dark at ambient temperature for 5 hours. Next, 1.5 ml of ethylene glycol was added to the reaction solution and stirred for 30 minutes. Thereafter, 2000 ml of acetone was gradually added to the reaction solution to precipitate aldehyde-oxidized hydroxyethyl cellulose. Further, the reaction mixture was left for 20-30 minutes to separate the liquid phase from the solid phase. Thereafter, the supernatant was removed and the solid phase was centrifuged to precipitate a solid. The solid precipitate was then dissolved in 100 ml DI overnight and then dialyzed for 72 hours. In addition, the final wet mixture was lyophilized to form a sponge / foam.

Example 3:
Preparation of CORC / HEC porous patch 2 g of hydroxyethyl cellulose (HEC, average molecular weight: 90 kD, from Aldrich) was dissolved in 98 g of deionized water. After the polymer was completely dissolved, 10 g of this HEC solution was transferred into a constant crystal dish having a diameter of 10 cm. Next, a surge cell Nu-Knit (registered trademark) absorbable hemostatic substance based on carboxyl oxidized regenerated cellulose (CORC) having a constant diameter of 9.8 cm (about 1.3 g) A piece was placed on the HEC solution in the crystallization dish. After soaking the fabric in solution for 3 minutes, the wet fabric in the dish was lyophilized overnight. As a result, a certain extremely flexible patch was formed. The patch was further dried at room temperature under vacuum. The ORC / HEC patch was then evaluated for hemostasis as described below. These results are shown in Table 2.

Example 4:
Preparation of CORC / MC porous patch 2 g of methylcellulose (MC, from Aldrich) was dissolved in 98 g of deionized water. After the polymer was completely dissolved, 10 g of this MC solution was transferred into a constant crystal dish having a diameter of 10 cm. Next, a piece of Surgicel Nu-Knit® fabric having a constant diameter of 9.8 cm (about 1.3 g) is placed on the MC solution in the crystallization dish. It was. After soaking the fabric for 3 minutes, the wet fabric in the dish was lyophilized overnight. As a result, a certain extremely flexible patch was formed. The patch was further dried at room temperature under vacuum. The CORC / MC patch was then evaluated for hemostasis as described below. These results are shown in Table 2.

Example 5:
Preparation of CORC / AOHEC porous patch 2 g of aldehyde oxidized hydroxyethyl cellulose (AOHEC) was dissolved in 98 g of deionized water. After the polymer was completely dissolved, 10 g of this AOHEC solution was transferred into a constant crystal dish having a diameter of 10 cm. Next, the Surge Cell Nu-Knit (registered trademark) absorbable hemostatic substance based on carboxyl oxidized regenerated cellulose (CORC) having a constant diameter of 9.8 cm (about 1.3 g) A piece was placed on the AOHEC solution in the crystallization dish. After soaking the fabric in solution for 3 minutes, the wet fabric in the dish was lyophilized overnight. As a result, a certain extremely flexible patch was formed. The patch was further dried at room temperature under vacuum. The CORC / AOHEC patch was then evaluated for hemostasis as described below. These results are shown in Table 2.

Example 6:
Preparation of CORC / AOMC porous patch 2 g of aldehyde oxidized methylcellulose (AOMC) was dissolved in 98 g of deionized water. After the polymer was completely dissolved, 10 g of this AOMC solution was transferred into a constant crystal dish having a diameter of 10 cm. Next, a piece of Surgicel Nu-Knit® fabric having a constant diameter of 9.8 cm (about 1.3 g) is placed on the AOMC solution in the crystallization dish. It was. After soaking the fabric for 3 minutes, the wet fabric in the dish was lyophilized overnight. As a result, a certain extremely flexible patch was formed. The patch was further dried at room temperature under vacuum. The ORC / AOMC patch was then evaluated for hemostasis as described below. These results are shown in Table 2.

Example 7:
Biodisintegration test of different materials Each 1 g sample according to Examples 3 to 5 was cultured in 100 ml PBS (phosphate buffered saline) buffer (pH 7.2). In addition, a piece of Surgicel Nu-Knit® fabric was used in a similar manner as a control article. After 48 to 72 hours, a clear pale yellowish fluid was obtained respectively. Next, size exclusion chromatography was performed on each solution to evaluate the molecular weight characteristics. This experiment was performed in duplicate. A constant TosohBiosep TSK G5000W × 1 SEC column and a RI detector at 40 ° C. were used with 0.15 M NaNO ₃ eluent. In addition, various polysaccharide standards were used for calibration. In the above set, the solution according to Example 3 has a higher molecular weight soluble polymer than the solution according to Example 5, this solution being a Surgicel Nu-Knit® fabric. It had more soluble polymer with a higher molecular weight than the control solution. This indicates that there is a collapse of the material according to Example 5 in the buffer.

Example 8:
Hemostasis ability of different materials in a porcine spleen incision model A constant porcine spleen incision model was used to evaluate the hemostasis of different materials. These materials are cut into a 2.5 cm × 1.5 cm rectangle. A 1.5 cm linear incision with a constant depth of 0.3 cm was made with a surgical blade in a porcine spleen. After delivery of the test article, finger tampon insertion was applied to the incision for 2 minutes. Thereafter, hemostasis was evaluated. In addition, additional applications of finger tampon insertion for 30 seconds each time were made until hemostasis was achieved. In this case, a fabric that could not stop hemostasis within 12 minutes was considered to be incapacitated. Table 2 below shows the results of this evaluation.

  As shown from the above results, the wound dressing of the present invention achieves effective hemostasis comparable to that of currently used hemostatic wound dressings and imparts biodegradability. It does not reduce the efficacy of hemostasis.

  The present invention is applicable to a hemostatic wound dressing that includes a fabric support that includes a first wound contact surface portion and the first wound contact surface portion. Having a second surface portion opposite to the wound contact surface portion, the fabric support comprising a plurality of fibers and further being effective in use as a hemostatic substance, It has strength and porosity, and the fabric contains a biocompatible polymer. The wound dressing further comprises a porous polymeric matrix, the polymeric matrix being distributed at least on the first wound contact surface portion and in the fabric support, In addition, the porous polymeric matrix contains certain biocompatible, biodegradable, water-soluble or water-swellable aldehyde oxidized polysaccharides.

Specific embodiments of the present invention are as follows.
(1) The wound dressing according to claim 1, wherein the fabric is woven or non-woven.
(2) The wound dressing according to claim 1, wherein the fabric is knitted.
(3) The wound dressing according to claim 1, wherein the fabric contains carboxyl-oxidized regenerated cellulose.
(4) The aldehyde-oxidized polysaccharide is cellulose, chitin, carboxymethyl chitin, hyaluronic acid, hyaluronic acid salt, alginate, alginic acid, propylene glycol alginate, glycogen, dextran, dextran sulfate, kurdran, pectin, pullulan, Xanthan, chondroitin, chondroitin sulfate, carboxymethyl dextran, carboxymethyl chitosan, heparin, heparin sulfate, heparan, heparan sulfate, dermatan sulfate, keratin sulfate, carrageenan, chitosan, starch, amylose, amylopectin, poly-N-glucosamine, polymannuron 2. Prepared with certain polysaccharides selected from the group consisting of acids, polyglucuronic acid, polyguluronic acid and derivatives thereof The placement of the wound dressing.
(5) The embodiment (4), wherein the polysaccharide comprises alkyl cellulose, hydroxyalkyl cellulose, alkylhydroxyalkyl cellulose, cellulose sulfate, a salt of carboxymethyl cellulose, carboxymethyl cellulose, and carboxyethyl cellulose. Wound dressing.
(6) the aldehyde-oxidized polysaccharide comprises an aldehyde-oxidized polysaccharide comprising a repeating unit of the following structural formula I:
In this case, x and y indicate mol% values, x + y is equal to 100%, x is from about 95 to about 5, y is from about 5 to about 95, R is CH ₂ OR ₃ , COOR ₄ , sulfonic acid, or phosphonic acid, R is H, alkyl, aryl, alkoxy, or aryloxy, and R ₁ and R ₂ are H, alkyl, aryl, alkoxy, aryloxy, sulfonyl, or phosphoryl The wound dressing according to claim 1, wherein the wound dressing is capable of.
(7) The wound dressing according to embodiment (6), wherein the aldehyde-modified polysaccharide is prepared from hydroxyethyl cellulose or ethyl cellulose.
(8) The wound dressing according to claim 1, wherein the weight ratio of the biodegradable, water-soluble or water-swellable aldehyde-modified polysaccharide to the fabric is about 1:99 to about 20:80.
(9) The wound dressing according to embodiment (7), wherein the weight ratio of the aldehyde-oxidized polysaccharide to the fabric is from about 3:97 to about 10:90.

It is the fixed scanning electron microscope image (75 times) of the cross section of the wound dressing of a fixed comparative example. It is the fixed scanning electron microscope image (75 times) of the cross section of the 1st surface part in the wound dressing of a fixed comparative example. It is the fixed scanning electron microscope image (75 times) of the cross section of the wound dressing of a fixed comparative example. It is a fixed scanning electron microscope image (75 times) of the 1st surface part in the wound dressing of a fixed comparative example. It is a fixed scanning electron microscope image (75 times) of the surface part of the 2nd opposite side in a wound dressing of a fixed comparative example. FIG. 3 is a constant scanning electron microscope image (75 ×) of a cross-section of a constant wound dressing of the present invention. FIG. 6 is a constant scanning electron microscope image (75 ×) of a surface portion for first wound contact in a wound dressing of the present invention. FIG. 3 is a constant scanning electron microscope image (75 ×) of a second opposite surface portion of a constant wound dressing of the present invention. FIG. 3 is a constant scanning electron microscope image (75 ×) of a cross-section of a constant wound dressing of the present invention. FIG. 6 is a constant scanning electron microscope image (75 ×) of a surface portion for first wound contact in a wound dressing of the present invention. FIG. 3 is a constant scanning electron microscope image (75 ×) of a second opposite surface portion of a constant wound dressing of the present invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Fabric 12 Cellulose fiber 14 Bundle of fibers 20 Fabric 22 Surface portion 23 for wound contact Fiber 24 Opposite surface portion 26 Polymer 30 Fabric 32 Surface portion for wound contact 33 Knitted fiber 34 Opposite surface portion 36 Polymer

Claims (1)

In the wound dressing for hemostasis,
A fabric support, the fabric having a first wound contact surface portion and a second surface portion opposite the first surface portion, the fabric further comprising a fiber; And has properties effective for use as a hemostatic substance, the fabric further comprises a biocompatible polymer, and the wound dressing further comprises:
A porous polymeric matrix distributed over the first wound contact surface portion and in the fabric, wherein the porous polymeric matrix is biocompatible; A wound dressing containing biodegradable, water-soluble or water-swellable aldehyde-oxidized polysaccharides.